RESUMO
This study investigated the effects of histamine H1 or H2 receptor antagonists on emotional memory consolidation in mice submitted to the elevated plus maze (EPM). The cerebellar vermis of male mice (Swiss albino) was implanted using a cannula guide. Three days after recovery, behavioral tests were performed in the EPM on 2 consecutive days (T1 and T2). Immediately after exposure to the EPM (T1), animals received a microinjection of saline (SAL) or the H1 antagonist chlorpheniramine (CPA; 0.016, 0.052, or 0.16 nmol/0.1 µL) in Experiment 1, and SAL or the H2 antagonist ranitidine (RA; 0.57, 2.85, or 5.7 nmol/0.1 µL) in Experiment 2. Twenty-four hours later, mice were reexposed to the EPM (T2) under the same experimental conditions but they did not receive any injection. Data were analyzed using one-way ANOVA and the Duncan test. In Experiment 1, mice microinjected with SAL and with CPA entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in T2, and there was no difference among groups. The results of Experiment 2 demonstrated that the values of %OAE and %OAT in T2 were lower compared to T1 for the groups that were microinjected with SAL and 2.85 nmol/0.1 µL RA. However, when animals were microinjected with 5.7 nmol/0.1 µL RA, they did not show a reduction in %OAE and %OAT. These results demonstrate that CPA did not affect behavior at the doses used in this study, while 5.7 nmol/0.1 µL RA induced impairment of memory consolidation in the EPM.
Assuntos
Vermis Cerebelar/efeitos dos fármacos , Clorfeniramina/farmacologia , Emoções/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Memória/efeitos dos fármacos , Ranitidina/farmacologia , Animais , Masculino , Memória/fisiologia , Camundongos , MicroinjeçõesRESUMO
This study investigated the effects of histamine H1 or H2 receptor antagonists on emotional memory consolidation in mice submitted to the elevated plus maze (EPM). The cerebellar vermis of male mice (Swiss albino) was implanted using a cannula guide. Three days after recovery, behavioral tests were performed in the EPM on 2 consecutive days (T1 and T2). Immediately after exposure to the EPM (T1), animals received a microinjection of saline (SAL) or the H1 antagonist chlorpheniramine (CPA; 0.016, 0.052, or 0.16 nmol/0.1 µL) in Experiment 1, and SAL or the H2 antagonist ranitidine (RA; 0.57, 2.85, or 5.7 nmol/0.1 µL) in Experiment 2. Twenty-four hours later, mice were reexposed to the EPM (T2) under the same experimental conditions but they did not receive any injection. Data were analyzed using one-way ANOVA and the Duncan test. In Experiment 1, mice microinjected with SAL and with CPA entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in T2, and there was no difference among groups. The results of Experiment 2 demonstrated that the values of %OAE and %OAT in T2 were lower compared to T1 for the groups that were microinjected with SAL and 2.85 nmol/0.1 µL RA. However, when animals were microinjected with 5.7 nmol/0.1 µL RA, they did not show a reduction in %OAE and %OAT. These results demonstrate that CPA did not affect behavior at the doses used in this study, while 5.7 nmol/0.1 µL RA induced impairment of memory consolidation in the EPM.
Assuntos
Animais , Masculino , Camundongos , Vermis Cerebelar/efeitos dos fármacos , Clorfeniramina/farmacologia , Emoções/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , /farmacologia , Memória/efeitos dos fármacos , Ranitidina/farmacologia , Microinjeções , Memória/fisiologiaRESUMO
This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.
Assuntos
Animais , Masculino , Camundongos , Ansiedade/induzido quimicamente , Benzotiazóis/farmacologia , Clorfeniramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , /farmacologia , Transtornos da Memória/induzido quimicamente , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Aprendizagem em Labirinto , MicroinjeçõesRESUMO
This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20â mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16â mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40â min, they were subjected to the EPM test. In T2 (24â h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8â mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16â mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8â mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.
Assuntos
Ansiedade/induzido quimicamente , Benzotiazóis/farmacologia , Clorfeniramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Transtornos da Memória/induzido quimicamente , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Animais , Masculino , Aprendizagem em Labirinto , Camundongos , MicroinjeçõesRESUMO
Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have high density in the vermis and flocculus. Evidence indicates that the cerebellar vermis is involved in memory consolidation. Recently, we demonstrated that when histamine is microinjected into the cerebellar vermis it results in impaired emotional memory consolidation in mice that are submitted to the elevated plus maze (EPM). This study investigated whether histamine impairment was mediated by the H(1) or H(2) receptors. The cerebellar vermis of male mice (Swiss Albino) were implanted using a guide cannula. Three days after recovery, behavioral tests were performed in the EPM on two consecutive days (Trial 1 and Trial 2). Immediately after exposure to the EPM (Trial 1), animals received a microinjection of histaminergic drugs. In Experiment 1, saline (SAL) or histamine (HA, 4.07 nmol/0.1 µl) was microinjected 5 min after pretreatment with the H(1) antagonist chlorpheniramine (CPA, 0.16 nmol/0.1µl) or SAL. In Experiment 2, SAL or HA was microinjected into the mice 5 min after pretreatment with the H(2) antagonist ranitidine (RA, 2.85 nmol/0.1 µl) or SAL. Twenty-four hours later, the mice were re-exposed to the EPM (Trial 2) under the same experimental conditions but did not receive an injection. On both days, the test sessions were recorded to enable analysis of the behavioral measures. The decrease in open arm exploration (% entries and % time spent in the open arms) in Trial 2 relative to Trial 1 was used as a measure of learning and memory. The data were analyzed using the two-way analysis of variance (ANOVA) and Duncan's tests. In Experiment 1, the Duncan's test indicated that the mice entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in Trial 2 after being microinjected with SAL+SAL, SAL+CPA and CPA+HA. However, the animals that received SAL+HA did not enter the open arms less frequently or spend less time in them, which was significantly different from the CPA+HA group. The results of Experiment 2 demonstrated that the %OAE and %OAT in Trial 2 were different from Trial 1 for the groups that were microinjected with SAL+SAL and SAL+RA. The animals that were microinjected with RA+HA or with SAL+HA did not show a reduction in %OAE. These results demonstrate that the animals treated with HA did not avoid the open arms less on retesting and indicated that CPA did not alter the behavior parameters but did revert the histamine-induced impairment of memory consolidation. Furthermore, the H(2) antagonist RA, at the dose used in this study, did not affect memory consolidation and failed to revert histamine-induced impairment.
Assuntos
Emoções/fisiologia , Histamina/administração & dosagem , Receptores Histamínicos H1/fisiologia , Receptores Histamínicos H2/fisiologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/fisiologia , Emoções/efeitos dos fármacos , Histamina/toxicidade , Antagonistas dos Receptores Histamínicos/administração & dosagem , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Camundongos , Microinjeções/métodosRESUMO
The biogenic amine histamine is an important neurotransmitter in the central nervous system that has been implicated in learning and memory processes. Experimental evidence indicates that the role of the cerebellum may be more complex than the simple regulation of motor responses, and recent studies have demonstrated significant involvement of the cerebellum in emotional memory consolidation. This study investigated the effect of histamine microinjected into the cerebellar vermis on emotional memory consolidation in mice in the elevated plus-maze (EPM). The cerebellar vermis of male mice (Swiss Albino) were implanted with guide cannulae. The mice weighed between 25 and 30 g. After three days of recovery, behavioral tests in the EPM were performed on two consecutive days; the testing periods were called, Trial 1 and Trial 2. Immediately after Trial 1, the animals received microinjections of histamine in the cerebellar vermis (0.54, 1.36, 2.72, and 4.07 nmol/0.1 µl). On both days, the test sessions were recorded to enable analysis of behavioral measures. The decrease in open arm exploration (% entries and % time spent in the open arms) in Trial 2 relative to Trial 1 was used as a measure of learning and memory. The data were analyzed using One-way Analysis of Variance (ANOVA) and Duncan's tests. The percentage of open arm entries (%OAE) and the percentage of time spent in the open arms (%OAT) were reduced in Trial 2 relative to Trial 1 for the control group; the same was true for the group that was microinjected with histamine at doses of 0.54 (%OAE and %OAT) and 1.36 nmol (%OAT). However, when the animals received histamine at doses of 2.72 and 4.07 nmol, their open arm exploration did not decrease. No significant changes were observed in the number of enclosed arm entries (EAE), an EPM index of general exploratory activity. These results suggest that there is a dose-dependent inhibitory effect of histamine microinjected into the cerebellar vermis on emotional memory consolidation.
Assuntos
Cerebelo/anatomia & histologia , Cerebelo/efeitos dos fármacos , Cerebelo/fisiologia , Emoções , Histamina/farmacologia , Memória/fisiologia , Animais , Comportamento Exploratório/efeitos dos fármacos , Histamina/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Microinjeções , Atividade Motora/efeitos dos fármacosRESUMO
The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean ± SEM; OAE: 4.0 ± 0.71, 4.80 ± 1.05; OAT: 40.55 ± 9.90, 51.55 ± 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 ± 0.73, 4.87 ± 0.66; OAT: 63.93 ± 11.72, 63.58 ± 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 ± 0.66, T2: 5.47 ± 1.05; T1: 63.58 ± 10.22; T2: 49.01 ± 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 ± 1.60, T2: 4.70 ± 1.04; T1: 51.55 ± 12.10, T2: 43.88 ± 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.
Assuntos
Animais , Masculino , Camundongos , Ratos , Ansiedade/induzido quimicamente , Histidina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologiaRESUMO
The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean +/- SEM; OAE: 4.0 +/- 0.71, 4.80 +/- 1.05; OAT: 40.55 +/- 9.90, 51.55 +/- 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 +/- 0.73, 4.87 +/- 0.66; OAT: 63.93 +/- 11.72, 63.58 +/- 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 +/- 0.66, T2: 5.47 +/- 1.05; T1: 63.58 +/- 10.22; T2: 49.01 +/- 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 +/- 1.60, T2: 4.70 +/- 1.04; T1: 51.55 +/- 12.10, T2: 43.88 +/- 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.
Assuntos
Ansiedade/induzido quimicamente , Histidina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , RatosRESUMO
RATIONALE: Mice exhibit antinociception after a single experience in the elevated plus maze (EPM), an animal model of anxiety. OBJECTIVE: This study investigated the mechanisms involved in this form of anxiety-induced antinociception. METHODS: Nociception was evaluated by means of the writhing test in mice confined either to the open or enclosed arms of the EPM. The effects of systemic (naloxone, midazolam and 8-OH-DPAT) or intra-amygdala (8-OH-DPAT, NAN-190 and midazolam) drug infusions were investigated in mice previously treated i.p. with 0.6% acetic acid, an algic stimulus that induces abdominal contortions. The effects of these drugs on conventional measures of anxiety (% entries and % time in open arms) in a standard EPM test were also independently investigated. RESULTS: Open-arm confinement resulted in a high-magnitude antinociception (minimum 85%, maximum 450%) compared with enclosed arm confinement. The opiate antagonist naloxone (1 mg/kg and 10 mg/kg) neither blocked this open arm-induced antinociception (OAIA) nor modified indices of anxiety in EPM. Administration of midazolam (0.5-2 mg/kg, s.c.) increased OAIA and produced antinociception in enclosed confined animals, as well as attenuating anxiety in the EPM. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.05-1 mg/kg, s.c.) had biphasic effects on OAIA, antagonising the response at the lowest dose and intensifying it at the highest dose. In addition, low doses of this agent reduced anxiety in the EPM. Although bilateral injections of 8-OH-DPAT (5.6 nmol/0.4 microl) or NAN-190 (5.6 nmol and 10 nmol/0.4 microl) into the amygdala did not alter OAIA, increased anxiety was observed in the EPM. In contrast, intra-amygdala administration of midazolam (10 nmol and 30 nmol/0.4 microl) blocked both OAIA and anxiety. CONCLUSIONS: These results with systemic and intracerebral drug infusion suggest that 5-HT(1A) receptors localised in the amygdala are not involved in the pain inhibitory processes that are "recruited" during aversive situations. However, activation of these receptors does phasically increase anxiety. Although the intrinsic antinociceptive properties of systemically administered midazolam confounded interpretation of its effects on OAIA, intra-amygdala injections of this compound suggest that benzodiazepine receptors in this brain region modulate both the antinociceptive and behavioural (anxiety) responses to the EPM.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Tonsila do Cerebelo/fisiologia , Analgesia/psicologia , Ansiolíticos/farmacologia , Ansiedade/psicologia , Midazolam/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Ansiolíticos/administração & dosagem , Masculino , Camundongos , Microinjeções , Midazolam/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagemRESUMO
Recent results from our laboratory have shown that 30-bites social conflict in mice produces a high-intensity, short-term analgesia which is attenuated by systemically injected 5-HT1A receptor agonists, such as BAY R 1531 (6-methoxy-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz((c,d)indole hydrochloride) and gepirone. The present study investigated the effects of these drugs, as well as the 5-HT1A receptor antagonist WAY 100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ) injected into the midbrain periaqueductal gray matter of mice on 30-bites analgesia. Four to five days after guide-cannula implantation, each mouse received microinjection of gepirone (30 nmol/0.2 microl), BAY R 1531 (10 nmol/0.2 microl), WAY 100135 (10 nmol/0.2 microl), saline (0.9% NaCl) or vehicle (saline + 4% Tween 80) 5 min before either an aggressive (30 bites) or a non-aggressive interaction. Nociception was assessed by the tail-flick test made before as well as 1, 5, 10 and 20 min after social interaction. The full 5-HT1A receptor agonist BAY R 1531 blocked, whereas, WAY 100135 and gepirone intensified 30-bites analgesia. Neither non-aggressive interaction, per se, nor the three compounds given after this type of social interaction significantly changed nociception. These results indicate that 5-HT1A receptors in the periaqueductal gray inhibit analgesia induced by social conflict in mice.